Journal
BRAIN RESEARCH
Volume 1795, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.brainres.2022.148073
Keywords
Seizure; Ferroptosis; GPX4; Lipid peroxidation; Seratrodast
Categories
Funding
- Guangzhou Municipal Science and Technology Project (CN) [202102080450]
- National Natural Science Foundation of China [81872743]
- High-level Hospital Construction Project of Guangdong project [K202104]
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More than 30% of epilepsy patients are unresponsive to current drugs, necessitating the development of new candidate drugs. Ferroptosis plays a crucial role in epileptic seizures and has potential as a drug target. Seratrodast, a market drug for thromboxane A2 receptor antagonist, has been discovered as a new ferroptosis inhibitor with potential therapeutic effects on seizures.
More than 30 % of individuals with epilepsy are refractory to currently available drugs, highlighting the urgent need to develop novel candidate drugs. Accumulating evidence implicates the key role of ferroptosis in the pathophysiology of epileptic seizures and its potential as a new drug target. Drug repurposing is a promising strategy for the rapid generation of new candidate drugs from the market drugs with new therapeutic indications, such as the best-selling drug thalidomide. Herein, we reported the discovery of Seratrodast, a market drug of thromboxane A2 receptor antagonist as a new ferroptosis inhibitor (IC50: 4.5 mu mol center dot L-1). Seratrodast could reduce lipid ROS production, regulate the system x(c)(-) /glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis, and inhibit JNK phosphorylation and p53 expression. In addition, Seratrodast elevated GPX4 expression and decreased JNK phosphorylation in pentylenetetrazole-induced seizures in mice. Seratrodast increased the latency of seizures and reduced seizure duration in pentylenetetrazole-induced seizures. Our results suggest Seratrodast might be either a ferroptosis inhibitor or a novel lead compound for further optimization of novel drug discovery.
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